3122 J. Org. Chem., Vol. 36, No. 9, 1970
BERGER,TELLER, AND PACHTER
Cycloalkapyrrolones wia Decarboxylative Ring Closure of Pyrrole-3-alkanoic Acids and Derivatives JOEL G. BERGER,SONIAR. TELLER, AND IRWIN J. PACHTER Endo Laboratories, Garden City, New York 11650 Received February 10, 1070 Acylation of pyrroles 1-2 with w-(methoxycarbony1)acylchlorides followed by catalytic reduction produces 3pyrrolealkanoic acid esters (4a-d) with chains bearing 3 and 4 methylene groups. Alkylation of malonic ester with quaternary salts of Mannich bases loa-c followed by hydrolysis and decarboxylation yields derivatives 4e-i and 14a-b with chains bearing 2 methylene groups. Treatment of these intermediates with polyphosphoric acid affords cycloalkapyrrolones of classes I11 and IV. One of these compounds, a 7-ketotetrahydroindole (S), was aromatized to produce the corresponding indol-Pol 9. The infrared and ultraviolet spectra and their relationship to structure are discussed.
Our interest in cycloalkapyrrolones stems from the finding that Mannich bases derived from 6,7-dihydroindol-4(5H)-ones (I) exhibit central nervous system depressant effects. The morpholino Mannich base I1 (molindone) has been found to be a potent antipsychotic agent in man.2
I
I1
I n order to study related systems we required appropriate cycloalkapyrrolones of classes I11 and IV. 0
II
I11
Iv
Although compounds of type I have been described13 little work has been done on systems included in I11 and lVa4 I n this paper we shall describe general synthetic routes t o these latter systems. It has been reported5 that compounds la-b undergo Friedel-Crafts acetylation. Accordingly, we found that acylations of l a and 2 with the acid chloride esters of succinic and glutaric acids give the keto diesters 3a-d easily and in good yield (Scheme I). (1) K. Schoen, I. J. Pachter, a n d A. A. Rubin, Abstracts, 153rd Nationad Meeting of the American Chemical Society, Miami, Fla., April 1967, No. M46. (2) A. A. Sugerman and J. Herrmann, Clin. Pharmacol. Ther., 8 , 261 (1967); G. M. Simpson and L. Krakov, Curr. Ther. Res. Clin. E x p . , 10, 41 (1968). (3) H. Stetter and R. Lauterbach, Justus Liebigs Ann. Chem., 666, 20 (1962); K. E. Schulte, J. Reisch, and H . Lang, Chem. Ber., 96, 1470 (1963); S. Hauptmann and M. Martin, Z . Chem., 8 , 333 (1968); J. M. Bobbitt and C. P. Dutta, Chem. Commun., 1429 (1968). (4) (a) M . E. Flaugh and H. Rappaport, J. Amer. Chem. Sac., 90, 6877 (1968), have reported preparation of a 4,5-dibydrocyclopenta [blpyrrol6(1H)-one. (b) A. J. Castro, et al., Abstracts, 158th Meeting of the American Chemical Society, New York, N. Y., Sept. 1969, No. ORGN 85, reported the isolation of 4,5-dihydroindol-7(6H)-onein very low yield from the reaction of pyrrolyl magnesium bromide with 4-chlorobutyronitrile. (c) The isolation of both 6,7-dihydroindol-4 (5H)-one and 4,5-dihydroindole7(6H)-one from the cyclization of the mixed carbonic anhydride of 4-(2pyrroly1)butyric acid has been recently reported. The conversion of these compounds t o the corresponding hydroxy indoles is also deacribed: M. Julia, French Patent 1540484 (1968); Chem. Abstr., 71, 8 1 1 6 3 ~(1969). (5) H. Fischer and E. Fink, Hoppe-Seyler’s Z . Physiol. Chem., 288, 152 (1948); H. Fischer and W. Kutscher, Justus Liebigs Ann. Chem., 481, 201 (1930).
The conversion of the esters 3a-d to the subsequent intermediates 4a-d requires selective reducing conditions. Ketopyrroles, which bear some chemical resemblance to vinylogous amides, are not reduced by sodium borohydrides. More drastic hydride reduction, as with diborane, can result in ester reduction as well as ketone r e d u c t i ~ n . ~ ~ ~ Wolff-Kishner reduction, when applied to compounds of type 3 (n = 2), has been found to result in pyridazine formation.* Catalytic hydrogenation under conditions of high temperature and pressure has been used to reduce ketopyrroles, some bearing ethoxycarbonyl groups on the pyrrole n u c l e u ~ . ~It seemed probable that the presence of electron-attracting ethoxycarbonyl groups would enhance the ketonic character of compounds 3a-d, making such drastic conditions unnecessary. Indeed, it was found that ketoalkanoic esters 3a-d underwent very rapid reduction and hydrogenolysis to yield esters 4a-d when subjected to the action of hydrogen at 50 psi at ambient temperatures in the presence of palladium on charcoal. I n all cases the theoretical uptake of hydrogen was complete within 2 hr, whereupon the reaction ceased. Reduced products were obtained in high yield. Regarding the cyclization of systems related to 4a-d, it was found that polyphosphoric acid (PPA) was a superior agent for the conversion of indole-3-alkanoic acids into cycloalka [b]ind~lones.~OAlthough indolealkanoic acids are stable materials, pyrrolealkanoic acids which lack electron-withdrawing substituents on the ring are relatively unstable compounds.l‘ The preparation and isolation of these compounds was avoided by generating them from 4a-d in situ in PPA a t 130-140”. Ester cleavage, decarboxylation, and ring closure occurred in one step to yield the six- and seven-membered cycloalkapyrrolones 5-8. Previous workers12 found that treatment of compounds of type I with Pd-C in high-boiling hydrocarbon (6) R. L. Hinman and 8. Thodoropoulous, J . O r g , Chem., 88, 3052 (1963), and references therein. (7) K. M. Biswas and A. H. Jackson, Tetrahedron, 24, 1145 (1967). (8) H. Fischer, H. Bayer, and E. Zaucker, Justus Liebigs Ann. Chem., 488, 55 (1931); H. Fischer and W. Kutscher, ibid., 481, 193 (1930). (9) F. K . Signaigo a n d H. Adkins, J . Amer. Chem. Soc., 68, 709 (1936); R . A. Nicolaus, G . Narni, M . Piatelli, and A. Vitale, Rend. Aocad. Sei. Pis. Mat., Naples, 26 [C], 135 (1959); Chem. Abstr., 6 6 , 14426f (1961). (10) K. Ishizumi, T. Shioiri, and S. Yamada, Chem. Pharm. Bull., 16, 863 (1967). (11) These compounds darken rapidly on exposure t o air and/or light: C f . H. Fischer and H . Orth, “Die Chemie des Pyrrols,” Akademische Verlag, Leipzig, 1934, pp 271-272. (12) W. A. Remers and M. J. Weiss, J . Amer. Chem. Soc., 87, 5262 (1965); H. Pleininger and K. Klinga, Chem. Ber., 101, 2605 (1968).
J. Org. Chem., Vol. 56, No. 9,1970 3123
CYCLOALKAPYRROLONES via RINGCLOSURE SCHEME I 0
II
CH3
R1
I I
t
a
HR 3 la, R, = C2H5;R, = CHJ;R3 = C02C2H5 b, R, = R, = CH,; R3= C02C2H5 2, R1 R3 = CH,; R2 = COZC2Hj R1
E
1
R1 H 3a, R, = C2Hj; R2 =CHJ; R3= C02C2H;,n = 2 b,R1= C,H,; R2 = CHj; R3 = COiCzH5; n = 3 c, Ri = CHj; R2= C02C2H,;R3= CH3; n = 2 d ,Rl = CH3; R2 = COLC2HB; R3 CH,; n = 3
C2H5
0 5
OH 9
1.
R 2 \ ~ c H 2 N ( c H 3 h
Rl’
CHJ
0
R3
loa, Rl = C2H5;R2 =CH3; R3= COpC2H, b,R1 = R2 =: CH,; R3 = COZCzHS C, R1= R3 CH3; Rz = COzC2HS
4a,R, C2H5;R2 = CH3;R3= C02C2H5R4= CH3;n = 2 b, R, = C2H,; R2 = CH3;R3= C02C2H,;R4 = CH3;n = 3 c, R, CH3;Rz = C02C2H5; R3 = CH3; R4 = CH3; n = 2 d, Rl=CH3;R*=COZC2HS;R3~CH3;Rp=CH3;n=3 R2 xCHzCH(C02R,)I e, R, = C,H,; R2= CH,; R3= C02C2H,;R4= H; n = 1 f , R1= CH3; R2 CH3; R3 = C02C2H5; R4 H n = 1 ?R1’ €I ‘R3 g, R, = CH3;R2= C02C2H,;R3= CH,; R, = H; n = 1 h, R, = C2H,; R, = CH3;R3= CO,H, R, = H n = 1 lla, R1 = C2H5;R2 =CH,; R3 = C02C2H5R4 = C2H5 i, R, = CH3; Rz= CH,; R3= C0,H; R4 H; t~ = 1 b, R1= CH3; R2 = CH3; R3 = COpC2Hb; R4 =C2H5 C, R,= CH3; R2 = C02C2H5; R3 = CH3; R4 = CzH, d, R, = C2H5;R2 = CH,; R3 C02C2H5;RI H R2mCH&HLQH e, R1 = CH3;R2 = CH3;R3= C02C2H,;Rp = H f, Rl =CH3; Rz = C02C2Hj;R3 = CH$ R4 = H R1 H H \ i.i
E
,
1
-1
12
13a, Rl = C2HB;R, = CH, b, R, = R2 = CH3
solvents aff ortled 4-hydroxyindoles. Similar treatment of 5 has been found to result in formation of the indol7-01 9, suggesting a useful synthetic route to these comp o u n d ~ . ~ cAttempts to aromatize 7 were unsuccessful. Next we undertook the synthesis of the cyclopentapyrrolones. I n reactions related to those which gave 3a-d, we found that l a with ethylmalonyl chloride resulted only in recovery of starting material. Consequently another method of elaborating the propionic acid side chain was sought. The observation has been madeIsa that the ethoxycarbonyl group in compounds of the type l a and lb exhibits a profound deactivating effect on the free p position toward electrophilic attack. While a later reportIab indicated that 2-methyl-5-carbethoxypyrrole3-propionic acid underwent the Mannich reaction with piperidine (but not with diethylamine or dimethylamine), this reactivity was attributed to stabilization of the product by inner salt formation, since the ethyl ester failed to react. We have found that both l a and lb readily undergo the Mannich reaction to give 10a and 10b in good yield. Compound 2 has been reported to (13) (a) 8. F. MacDonrld, J . Chem. Soc., 4178 (1952); (b) A. Triebs and W. Ott, Justus Liebigs Ann. Chem., 616, 137 (1958).
undergo the Mannich reaction with diethylamine and piperidine,I4 although the products were described only as their perchlorate salts. Attempts to free the bases from these salts were reported to be unsuccessful. I n our hands no difficulty was experienced in preparing 1Oc from 2. Quaternization of loa-c with methyl sulfate, followed by treatment with sodiomalonic ester gave the corresponding substituted malonic esters 1 la-c.16 These esters could be selectively hydrolyzed to the free malonic acids 1 Id-f by refluxing briefly with methanolic KOH. Decarboxylation to give 4e-g was effected by heating above the melting point until cessation of gas evolution. Acid ester 4g was converted directly to 12 by heating with PPA. Hydrolysis of 4e and 4f to the dicarboxylic acids 4h and 4i was effected by heating with aqueous alkali. The diacids, which were isolated but not characterized, were decarboxylated by heating briefly in water on the steam bath to give the pyrrolepropionic acids 14a and 14b. This sequence of reactions for preparing these important pyrrole derivatives may be considered as an (14) H.Firrcher and C. Nenitaescu, ibid., 448, 113 (1925). (15) W. Hem end R. L. Settine, J . Org. Chem., 94, 201 (1959).
3124 J . Org. Chem., Vol. 36,No. 9, 1970
BERGER,TELLER, AND PACHTER
TABLEI CARBONYL STRETCHING FREQUENCIES OF CYCLOALKAPYRROLONES~ Ring size
Cycloalka[b] series
Compd
5 5 6 7
Cycloalka[cl series
vc-0,
13b 5 6
2-Acetyl3,4,5-trimethylpyrrole 2-Acetyl-3,4-dimethyl5-n-propyipyrrole 12 7
5 6
7
1624b 1630 1690~ 1663 1650
8
3-Acetyl2,4,5-trimethylpyrrole a
5X
M in CClr.
Reference 17.
om-1
1657 1658 1643,1630 1612
13a
16576
1.8 X 10-8 M .
TABLE I1 ULTRAVIOLET SPECTRA OF CYCLOALKAPYRROLONES~ Ring size
Cycloalka[b] series
Compd
5
13b
6
5
7
6
2-A cetyl-3,5dimethyl-4-ethylpyrrole Cycloalka[c] series
12
7 8
3-Acetyl-2,5-dimethyl4-n-propylpyrrole Solvent ethanol.
b
108,
e
292 257.5 305.5 26Sb 314 270b 308 266b
20.2 7.68 19.6 5.82 16.7 5.37 19.6 4.70
0
305 250 306 254 302 253.5 296 253.5
3.81 13.4 3.98 11.5 3.73 8.85 4.56 10.7
Amax,
mp
10 24 10 0
22 35 27
Shoulder.
alternate to several described in the l i t e r a t ~ r e ' ~which ,'~ ketone 5 is observed. This behavior was also noted with the six-membered ketones in the indolone series.lBa are very laborious and/or require difficultly accessible The ultraviolet spectra of the cycloalkapyrrolones starting materials. The 2,3-dialkyl-5-ethoxycarbonylpyrroles required for our scheme are easily a ~ a i l a b l e . ~ , ~(Table 11) show behavior which conforms t o a general PPA proved useful for the cyclization of 14a-b and the pattern previously establi~hed'~ for pyrroles substituted with -n!I substituents. I n both series, the intensity of five-membered cycloalkapyrrolones 13a-b were synthesized. the major band is decreased with increasing ring size. This effect may be attributed to the inhibition of coIt has been shown that" the carbonyl stretching freplanarity of the carbonyl group with the pyrrole ring quency of 2-acylpyrroles in dilute carbon tetrachloride by nonbonded interactions in the saturated ring, which solution is appreciably lower than that of the 3-acyl increase with increasing ring size. This effect has alderivatives. This effect is presumably due to intraready been noticed in the previously mentioned cyclomolecular hydrogen bonding, and is shown by the cycloalka [b ]indolones,18&which provides an interesting paralalkapyrrolones (Table I). I n addition, a lowering of lel to the present work. the carbonyl stretching frequency is noted in going from By use of the cos26 rulelZothe angle B by which the the five- to the seven-membered cycloalkapyrrolones. carbonyl group is twisted out of the plane of the aroThis behavior is parallel to that observed for a series of matic ring may be approximated. For the cycloalkaclosely related cycloalka [ b ] i n d o l o n e ~as ,~~ well ~ as the [bjpyrrolones these angles are considerably smaller benzocyclanones,lsb and was attributed to changes in the C-0 bond character with increasing bond angle. lSb than in the corresponding cycloalka [blindolones.lSa A splitting of the carbonyl band of the six-membered This may be rationalized by postulating that canonical forms of the cycloalka[b]pyrrolones such as V are important contributors to the total structure of 111, (16) (a) H. Plieninger, P . Hess, and J. Rupert, Chem. Ber., 101, 240 (1968); (b) F. Morsingh and S, F. hlacDonald, J . Amer. Chem. Soc., Ea, whereas forms such asVI are not as important to the total 4377 (1960). (17) R . W. Guy and R . A. Jones, Aust. J . Chem., 19, 107 (1966). (18) (a) T. Shioiri, K. Ishizumi, and 8. Yamada, Chem. Pharm. Bull., 16, 1010 (1967); (b) W. M. Schubert and W. A. Sweeney, J . Amer. Chem. Soo., 77, 4172 (1955).
(19) U.Eisner snd P. H. Gore, J . Chem. Soc., 922 (1958). (20) ,os% e = f / P , where 8 is the extinction coefficient for the planar homolog (0 = 0 " ) : E. A. Braude and F. Sondheimer, J . Chem. SOC.,3754 (1955).
CYCLOALKAPYRROLONES via RINGCLOSURE
J . Org. Chem., VoZ. 35,No. 9, i970 3125
Methyl 2-Ethoxycarbonyl-5-ethyl-4-methylpyrrole-3-butyrate (4a).-A solution of 3a (59 g, 0.2 mol) in 250 ml of abs ethanol was hydrogenated over 10 g of 10% Pd-C at 50 psi in a Parr apparatus a t room temperature. Uptake of hydrogen (98% of theory) was complete after 2 hr. Catalyst was filtered off and the filtrate evaporated to give a colorless oil which soon solidified. Recrystallization from ether-petroleum ether (30-60') gave white needles (35.5 g, 63%): mp 65-67'; ir (Nujol) 5.73 (aliphatic ester), 6.01 p (pyrrole ester). Anal. Calcd for C16HzaN04: C, 64.03; H, 8.24; N,4.98. Found: C, 63.75; H, 8.30; N , 4.87. Methyl 2-Ethoxycarbonyl-5-ethyl-4-methylpyrrole-3-valerate (4b).-From 3b in 85% yield as white crystals from pentane, mp 34-36'. Anal. Calcd for CleH26N04: C, 65.06; H , 8.53; N, 4.74. Found: C, 64.89; H, 8.71; N , 4.67. Methyl 4-Ethoxycarbonyl-2,5-dimethylpyrrole-4-butyrate (4c). I -From 3c in 78% yield as white crystals from ether, mp 85.56V086.5'. Anal. Calcd for C14H21NO4: C, 62.90; H, 7.92; N, V VI VI1 5.24. Found: C,62.91: H , 7.80; N , 5.18. Methyl 4-Ethoxycarbonyl-2,5-dimethylpyrrole-3-valerate (4d). The absorption bands of the type I11 ketones exhibit From 3d in 71 % yield as white crystals from benzene-hexane, mp 45.5-47.5'. Anal. Calcd for C16HzaN04: C, 64.03; H, 8.24; concomitant bathochromic and hypochromic effects N,4.98. Found: C, 64.15; H,8.22; N,4.91. with increasing ring size, behavior typical of nonalterEthyl 3-(Dimethylamino)methyl-5-ethyl-4-methylpyrrole-2-carnant aromatic systems.21 However, the type IV keboxylate (loa).-A mixture of ethyl 5-ethyl-4-methylpyrroletones show spectral behavior which is more typical of 2-carboxylate (270 g, 1.5 mol), 36% aqueous formaldehyde (125 alternant systems such as the benzocyclanones.22 It is ml, 1.5 mol), and anhydrous dimethylamine (67.5 g, 1.5 mol) in 2 1. of ethanol was heated a t 80-95' under a nitrogen atmosphere in a of interest to note that open-chain trisubstituted pyrrole 3 1. steel bomb for 16 hr. The contents of the bomb were then ketones are also apparently twisted out of plane. evaporated in vacuo, the residue was taken up in ether and exThe nmr spectrum of compound 5 (see Experimental tracted with several portions of 2 N HC1. Work-up of the ether Section) was determined and appears consistent with layer gave 81 g of recovered starting material. The acid extracts were basified with NaOH, and the prethe proposed structure. cipitated oil was extracted into ether. The extracts were washed with water, dried over anhydrous KzCO~,and evaporated to yield a dark oil which quickly crystallized. Recrystallization Experimental Section28 from pentane gave white needles (169.2 g), mp 76-78". The Methyl 2-Ethoxycarbonyl-5-ethyl-4-methyl-~-oxopy~ole-3-b~recovered starting material was recycled to give another 67.3 g of tyrate (3a).-Aluminum chloride (200 g, 1.5 mol) was added product, total yield 66%. Anal. Calcd for C~SHZZNZOZ: in large portions to a solution of ethyl 2-ethyl-3-methylpyrrole-5- C, 65.51; H, 9.31; N, 11.76. Found: C, 65.57; H , 9.38; N , carboxylate (136 g, 0.75 mol) and methyl 3-(chloroformy1)11.86. propionate (Aldrich, 450 g, 3.0 mol) in 2.2 1. of carbon disulfide Ethyl 3-(Dimethylamino)methyl-4,5-dimethylpyrrole-2-carboxcontained in a 5-1. 3-necked flask equipped with a mechanical ylate (lob).-From lb as above in 45% yield. Thick staffs stirrer and a reflux condenser topped with a CaC12 drying tube. from pentane, mp 87-89'. Anal. Calcd for CIZHZONZOZ: C, The stirred mixture was gently heated a t reflux for 4 hr during 64.25; H, 8.99; N , 12.49. Found: C, 64.19; H , 9.00; N, which time a gummy brown reaction complex separated. After 12.35. cooling the mixture to room temperature, the CSZwas decanted Ethyl 4-(Dimethylamino)methyl-2,5-dimethylpyrrole-3-carboxand the remaining complex decomposed with ice. The solid ylate (10c).-From 2 as above in 68% yield. Pale yellow product which separated was filtered off, dissolved in benzene, crystals from benzene-hexane, mp 111-113'. Anal. Calcd for and washed with NazCOs solution, then with saturated NaCl. C12H20NzOz: C, 64.25; H, 8.99; N, 12.49. Found: C, 64.43; The solution was then dried over MgSO4, the solvent removed H, 9.02; N, 12.59. in vacuo, and the residue recrystallized from methanol-water Diethyl [ (2-Ethoxycarbonyl-5-ethyl-4-methylpyrrol-3-yl)methyl] to give 175 g (78%;)of material: mp 70-72'; ir (Nujol) 5.75 (alimalonate (lla).-Dimethyl sulfate (126 g, 1.0 mol) was slowly phatic ester), 5.89 (pyrrole ketone), 6.01 p (pyrrole ester). added to a solution of 10a (238 g, 1.0 mol) in 550 ml of ethanol. Anal. Calcd for C16HalN06: C, 61.00; H, 7.17; N, 4.74. The solution warmed and was allowed to stand for 2 hr before Found: C, 61.06; H , 7.08; N , 4.54. adding a freshly prepared solution of sodio diethyl malonate Methyl 2-etlioxycarbonyld-ethyl-4-methyl-6-oxopyrrole-3-val- (from sodium (28.6 g, 1.25 g-atom) and diethyl malonate (190 erate (3b) was prepared from l a and methyl 4-(chloroformy1)ml, 1.25 mol) in 500 ml of ethanol. The resulting mixture was butyrate as above in 84% yield. Colorless needles from hexane, then allowed to stand a t room temperature for 3.5 days. mp 38-39.5". Anal. Calcd for CI~HZSNO~: C, 62.12; H , Alcohol was then removed in vacuo, and the residue treated 7.49; N,4.53: Found: C,62.17; H, 7.51; N , 4.53. with benzene and water. The benzene layer was separated, Methyl 4-Ethoxycarbonyl-2,5-dimethyl-~-oxopyrrole-3-butyrate extracted with 1 N HCl, washed with water, and dried (MgS04). (3c).-From 2 as described for 3a in 757&yield. The compound Removal of solvent left a pale yellow oil which soon solidified, was obtained a8 an oil which solidified to a crystalline material and was recrystallized from pentane. Thusly was obtained 227 mp 53-56' upon standing in moist air. Attempts to dry the g (64%) of white needles, mp 46-48'. Anal. Calcd for ClsHZTsolid in vacuo a t 25' resulted in reconversion to an oil. A NOa: C, 61.17; H , 7.70; N, 3.96. Found: C, 60.94; H , satisfactory analysis could not be obtained. 7.63; N, 3.87. Methyl 4-Ethoxycarbonyl-2,5-dimethyl-6-oxopy~ole-3-valerate Treatment of this material (70.6 g) with 600 ml of 20% meth(3d).-From 2 in 95% yield as a yellow oil which failed to crystalanolic potassium hydroxide gave an initially clear solution, lize. which began to deposit a voluminous white solid within 5 min at room temperature. This mixture was warmed at reflux for (21) H. H. Jaffe and M . Orchin, "Theory and Applications of Ultraviolet 15 min and the potassium salt filtered off, washed with some cold Spectrosoopy," Wiley. New York, N. Y., 1962, pp 434-437. (22) G. D. Hedden and W. G. Brown, J . Amsr. Chsm. Sac., '?&, 3744 methanol and dissolved in 600 ml of water. A stream of SO2 gas (1953). was passed into the solution until pH 3 was reached. The pre(23) Melting points are uncorreoted. Mioroanalyses were performed by cipitated acid ( l l d ) was filtered off and dried to give 48 g (81%) the Spang Microanalytical Laboratory, Ann Arbor, Mich. Infrared spectra of white crystals, mp 170-171' dec; 80.5 mg required 5.72 ml of as Nujol mulls were determined on a Perkin-Elmer Model 137 Infracord. 0.1 N NaOH (neutralequiv 140.5, theory 148.5). Solution spectra were determined in 1.0-mm matohed NaCl cells on a PerkinDiethyl [ (2-Ethoxycarbonyl)-4,5-dimethylpyrrol-3-yl)methyl] Elmer Model 221 spectrophotometer. Ultraviolet spectra were determined malonate (lib).-From 10b in 6970 yield. Needles from penon a Cary 14 recording spectrophotometer. Nrnr spectra were determined; oourtesy of Dr. J. Swinehart of the Perkin-Elmer Laboratories, Norwalk, tane, mp 55-56.5'. Anal. Calcd for C17Hz6NOa: C, 60.16; H , Conn. on a Model R-12 spectrometer. 7.43; N,4.13. Found: C, 60.18; H,7.40; N,4.16.
picture of the cycloalkaindolones since this structure requires disturbance of benzenoid resonance. This concept has already been employed to explain differences in chemical reactivity between pyrroles and ind o l e ~ . Application ~ of the cos28 rule to the cycloalka[ c ] series yields angles which are in the same range as those of the cycloalka [b]indolones, indicating that form VI1 is a less significant contributor to IV.
3126 J. Org. Chem., VoE. 56, No. 9,1970 This material was hydrolyzed to the corresponding malonic acid (lle), mp 169-170' dec, which was not further characterized. Diethyl [ (4-Ethoxycarbonyl-2,5-dimethylpyrrol-3-y1)methyl] malonate (llc).-From 1Oc in 51y0 yield. White crystals from 80% ethanol, mp 75-76'. Anal. Calcd for C I ~ H ~ ~ NC, O~: 60.16; H, 7.43; N, 4.13. Found: C, 60.22; H, 7.41; N, 4.17. Hydrolysis gave l l f , mp 155-157' dec. 2-Ethoxycarbonyl-5-ethyl-4-methylpyrrole-3-propionic Acid (4e).-Decarboxylation of 1Id was effected by heating the compound (48 g) in an Erlenmeyer flask immersed in an oil bath a t 190-200' until evolution of COZwas complete (10-15 min). The liquid product was allowed to solidify and was then scraped out of the flask, giving 40.2 g (98%) of crude 4e. An analytical sample was recrystallized from ethanol-water as long needles, mp 145.5-147.5'; ir (Nujol) 5.84 (COOH), 6.01 (pyrrole ester). Anal. Calcd for ClaH1ONOd: C, 61.64; H , 7.56; N, 5.53. Found: C, 61.58; H I 7.57; N, 5.53. 2-Ethoxycarbonyl-4,5-dimethylpyrrole-3-propionicAcid (4f).From lle. Needles from ethanol-water, mp 155-157'. Anal. Calcd for Cl2HI7NOI: C, 60.24; H , 7.16; N, 5.86. Found: C, 60.14; H I 7.09; N, 5.83. 4-Ethoxycarbonyl-2,5-dimethylpyrrole-3-propionicAcid (4g).From l l f . Needles from ethanol-water, mp 172-175'. Anal. Calcd for C12H17N0,: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.27; H , 7.23; N, 5.83. 2-Ethyl-3-methylpyrrole-4-propionicAcid ( 14a).-The above described crude 4e was heated for 1 hr at reflux with 250 mI of 20% aqueous potassium hydroxide. The mixture was then cooled and diluted with 250 ml of water; a stream of SO2 gas was passed into the solution until pH 3 was obtained. Precipitated solid (4h) was filtered off and the filtrate extracted with ether. The ether extracts were evaporated, leaving a yellow oil which was combined with the filtered solids, moistened with some water, and heated on the steam bath until gas evolution was complete. Water was removed from the resulting product on the rotary evaporator and the residue extracted with several portions of boiling hexane totalling 2.5 1. On cooling, long colorless needles of 14a formed, which were filtered off and dried. There was obtained 24.4 g (85%) of product, mp 83-84.5' [lite2*mp 85-88']. 2,3-Dimethylpyrrole-4-propionic Acid (Haemopyrrolecarboxylic Acid, (14b).-Prepared as above from 4f, mp 126.5-127.5 [lit.IBb mp 127-129'1. 2-Ethyl-4,5-dihydro-3-methylindol-7(6H)-one (5).-The diester 4a (31 g) and 458 g of polyphosphoric acid were heated slowly to 125-130'. Frothing commenced a t about 80' and the mixture was stirred vigorously with a glass rod to prevent overflow. The dark mixture was heated for 30 min after the frothing had ended, cooled to 60', and poured into a large volume of cold water. After stirring to dissolve the polyphosphoric acid, the mixture was chilled in ice for 30 min; the solid product was filtered off and thoroughly washed with water. After drying, the highly colored crude product was sublimed a t 125' (0.1 mm) to give white crystals (8.8 g, 45y0 yield). An analytical sample was (24) V. L. Archibald, D. M . Walker, K. B. Shaw, A. Markovec, and 8. F. MacDoneld, Can. J . Chena., 44, 345 (1866).
BERQER, TELLER, AND PACHTER recrystallized from ether-hexane, mp 135-136'; nmr (CDCl,) 6 1.18 (t, 3, J = 7 Hz, CHrCHz), 1.89 ( 8 , 3, CHs-), 1.96-2.82 (m, 8, combined -CH2-). Anal. Calcd for C11H16NO: C, 74.54; H,8.53; N,7.90. Found: C, 74.44; C,8.41; N , 7.93, The following ketopyrroles were prepared as above using a 15 fold excess of PPA: 2-ethyl-4,5,6,7-tetrahydro-3-methylcyclohepta[b]pyrrol-8(1H)-one (6). From 4b in 17% yield. Needles from hexane, mp 120-121'. Anal. Calcd for C12H1,NO: C, 75.35; H, 8.96; N, 7.32. Found: C, 75.30; H I 9.05; N, 7.35. 6,7-Dihydro-1,3-dimethylisoindol-4(5H)-one(7).-From 4c in 65% yield. Crystals from methanol, mp 151-152' (lit.26 mp 151-152'). Anal. Calcd for CioHiaNO: C, 73.59; H, 8.03; N, 8.58. Found: C, 73.75; H, 7.97; N, 8.64. 5,6,7,8-Tetrahydro-1,3-dimethylcyclohepta[c] pyrroL4(2H)-one (8).-From 4d in 28% yield. Needles from hexane-benzene, mp 136-138". Anal. Calcd for C11HiSNO: C, 74.54; H, 8.53; N, 7.01'. Found: C, 74.56; H, 8.52; N, 6.90. 2-Ethyl-4,5-dihydro-3-methylcyclopenta [b]pyrrol-6(1H)-one (13a).-From 14a in 62% yield. Rhombs from hexane, mp 179.5-181.5'. Anal. Calcd for CloHirtNO: C, 73.59; H , 8.03; N, 8.58. Found: C,73.55; H,8.01; N,8.64. 4,5-Dihydro-2,3-dimethylcyclopenta[b]pyrrol-6(lH)-one (13b). -From 14b in 67% yield. Microcrystals from hexane, mp 223223.5'. Ana[. Calcd for CBH1lNO: C, 72.45; H , 7.43; N, 9.39. Found: C, 72.53; HI 7.33; N, 9.40. 5,6-Dihydro-l,3-dimethylcyclopenta[c] pyrrol-4(2H)-one (12),From 4g in 38% yield. Feathers from toluene, mp 244-246' ( k Z 6 mp 245-248' dec). Anal. Calcd for CsHllNO: C, 72.45; 7.43; N, 9.39. Found: C, 72.30; H, 7.62; N, 9.42. 2-Ethyl-3-methylindol-7-01 @).-A mixture of 5 (3.8 g), 10% Pd-C (4.0 g), and 125 ml of cumene was heated with stirring a t reflux under nitrogen for 20 hr. The hot reaction mixture was then filtered, and the solvent evaporated in vacuo to give a light orange residue (2.7 g) which solidified on trituration under pentane. Recrystallization from hexane gave white needles, mp 86-88', soluble in 1 N NaOH and giving a violet color with FeCla solution. Ultraviolet spectrum (MeOH): 293 (5075), 271 mp (7884). Anal. Calcd for CliHiaNO: C, 76.40; H, 7.48; N, 7.99. Found: C,75.13; H,7.55; N,8.02.
Registry N0.-3a, 25109-99-3; 3b, 25110-00-3; 3c, 25110-01-4; 4a, 25110-02-5; 4b, 25110-03-6; 4c, 25110-04-7; 4d, 25110-05-8; 4e, 25110-06-9; 4f, 25110-07-0; 4g, 6315-16-8; 5,25110-09-2; 6,25158-241; 7, 21770-35-4; 8, 25110-11-6; 9, 25158-25-2; loa, 25110-12-7; lob, 25110-13-8; lOc, 25110-14-9; lla, 25110-15-0; l l b , 25158-26-3; l l c , 25158-27-4; l l d , 25110-16-1; 12, 21770-33-2; 13a, 25110-18-3; 13b, 25110-19-4; 2-acetyl-3,4,5-trimethylpyrrole1 22186-841 ; 2-acetyl-3,4-dimethyl-5-n-propylpyrrole, 251 10-21-8 ; 3-acetyl-2,4,5-trimethylpyrrole, 19005-95-9; 2-acetyl3,5-dimethyl-4-ethylpyrrole,1500-91-0; 3-acetyl-2,5dimethyl-4-n-propylpyrrole, 10594-44-2. (25) I. J. Paohter and W. Hera, U. S. Patent 3, 415, 843 (1868).
